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Medical Journal of Zambia, Vol. 46 (2): 133 - 139 (2019)

Original Article Prophylactic Use of Trihexyphenidyl (Artane) in Schizophrenia and Psychosis: A Critical Review of Literature to Guide for Evidence Based Practice in Zambia

W. A. Sheikh Department of Psychiatry, Livingstone Central Hospital, Livingstone

ABSTRACT Conclusion: There is generally no need to start an drugs when a patient is prescribed Background: Anticholinergic drugs are particularly . For patients who are already on used in psychiatric practice to counteract the EPS anticholinergic drugs, discontinuation of these drugs secondary to drugs. Trihexyphenidyl should be considered in patients with stable EPS. (Benzhexol), commonly known as 'Artane' is most Anticholinergic drugs can be considered only in widely used anticholinergic drug in Zambia. It is individuals with significant EPS when dose routinely prescribed as prophylaxis to counteract the reduction and switching strategies have proven side-effects in patients taking FGA. In anecdotal ineffective, or when the side effects are acute or experience the abuse of artane is very common severe. among mental patients as well as in the general public in Zambia. This article reviews the literature INTRODUCTION about psychiatric use, mechanism of action and abuse potential of trihexyphenidyl. Schizophrenia is one of the most serious and debilitating psychiatric illness with life time Objective: This review aim to critically review the prevalence of about 1% round the globe.1,2 It is literature about use of trihexyphenidyl to guide characterized by positive, negative, cognitive and whether it is justified to use this drug for prophylaxis affective symptoms. Since the introduction of to counteract the side-effects of antipsychotics in in 1952, antipsychotic drugs Zambia. represent the mainstay of the pharmacological treatment for psychosis and schizophrenia.2,3,4 Exact Methodology: Literature search was conducted pathophysiological mechanisms underlying using MEDLINE via PubMed (from 1970- schizophrenia are unknown but consistent evidence 2018).Initially broad search was undertaken to find points to an increased subcortical presynaptic controlled studies, case reports and review articles neurotransmission. 2 , 5 On this and later some relevant bibliographic articles were neurochemical basis, all antipsychotics are reviewed to find some more studies. dopamine D2 receptor antagonists. By blocking neurotransmission in subcortical Corresponding author: areas, they are capable of producing extra- Waqas Ahmed Sheikh Department of Psychiatry, Livingstone Central Hospital, pyramidal side-effects (EPS), such as P.O. Box 60091 Livingstone-Zambia Phone number: +260977796947, Key Words: Antipsychotics, Schizophrenia, Trihexyphenidyl, E. mail: [email protected] Zambia

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(tremor, akinesia and rigidity), akathesia, OBJECTIVE and tardive (TD), occurring acutely or during chronic treatment.2,4 In general, this This review aim to critically review the literature propensity is more pronounced with the first- about use of trihexyphenidyl to guide whether it is generation antipsychotics (FGA) than with the justified to use this drug for prophylaxis to second generation antipsychotics (SGA).2,6 In the counteract the side-effects of antipsychotics in past 2 decades, SGA replaced FGA as the standard Zambia. treatment for schizophrenia in many parts of the METHODOLOGY world although there is recent evidence indicating no differences in their effectiveness.2,6 In Zambia Literature search was conducted using MEDLINE FGA like haloperidol, chlorpromazine, via PubMed (from 1970-2018) and using the key trifluoperazine, and fluphenazine decanoate are still words: used as first line treatments for psychosis and Trihexyphenidyl, benzhexol, artane, anticholinergic schizophrenia at all public clinics and hospitals. drugs, first and second generation antipsychotics, SGA like risperidone, etc. are available in schizophrenia, antiparkinsonian drugs, use, and public sector at teaching hospitals as 2nd line misuse. treatments but most of the SGA are available in Initially broad search was undertaken to find private sector. controlled studies, case reports and review articles Anticholinergic drugs are particularly used in and later some relevant bibliographic articles were psychiatric practice to counteract the EPS secondary reviewed to find some more studies. to antipsychotic drugs. 7 , 8 Trihexyphenidyl PHARMACOLOGY OF TRIHEXYPHENIDYL (Benzhexol), commonly known as 'Artane' is most widely used anticholinergic drug in Zambia. (Ach) is an excitatory Trihexyphenidyl is routinely prescribed as neurotransmitter in the brain and has multiple prophylaxis to counteract the side-effects in patients physiological functions in the nervous system.8 Ach taking FGA. In anecdotal experience the abuse of exerts its effects by binding two major subtypes of artane is very common among mental patients as receptors: the metabotropic muscarinic receptors14 well as in the general public in Zambia. and inotropic nicotinic receptors.15 Anticholinergic abuse has been reported in many Dopamine and Ach have reciprocal relationship with clinical settings particularly in patients with severe each other in the nigrostriatal pathway. Dopamine mental illness, where the prevalence of misuse could normally inhibit Ach release from postsynaptic reach 34%. 7 , 1 1 In a 2008 news report, nigrostriatal neurons, thus suppressing 8 “trihexyphenidyl was seen to be used for Ach activity there (Figure 1). recreational purposes among Iraqi soldiers and police, among other prescription drugs. The report states that the drugs were taken to relieve combat stress.”12 Different studies revealed that the purpose of abuse is to achieve a euphoric state and to enhance social skills.13 This article reviews the literature about psychiatric use, mechanism of action and abuse potential of trihexyphenidyl.

FIGURE 1, Reciprocal Relationship of Dopamine and Acetylcholine.8

134 Medical Journal of Zambia, Vol. 46 (2): 133 - 139 (2019)

If dopamine receptors are blocked by FGA, then On the other hand, trihexyphenidyl also act as a dopamine can no longer suppress Ach release, so potent indirect .7,16 in the limbic Ach becomes overly active, and produce system, which is a set of interconnected brain EPS8(Figure 2).9 structures including the nucleus accumbens and the ventral tegmental area, involved in motivation, learning, memory and reward. This can in part explain the abuse potential of trihexyphenidyl in both psychiatric and non-psychiatric patients.7

PROPHYLACTIC USE OF TRIHEXYPHENIDYL

Anticholinergic agents like trihexyphenidyl have long been considered the treatment and prophylaxis of choice for antipsychotic-induced EPS. The EPS treated with trihexyphenidyl include Parkinsonism (tremors, rigidity& bradykinesia) and acute dystonia.17 Trihexyphenidyl however is known to FIGURE 2, Dopamine, Acetylcholine and D2 worsen TD. 1 8 Xerostomia, blurred vision, Antagonism.9 xerophthalmia, and flushed skin are the 19,20 One compensation for this over activity of Ach is to common side effects of trihexyphenidyl. Delayed block it with anticholinergic agent like micturition, urinary retention and sexual trihexyphenidyl. Thus trihexyphenidyl will dysfunction are occasionally seen.19,20 A more diminish the excess Ach activity caused by removal worrisome effect often seen in aging patients is of dopamine inhibition when dopamine receptors cognitive impairment.20,21Abuse of anticholinergic are blocked by FGA8 (Figure 3).10 drugs like trihexyphenidyl can lead to euphoria and psychosis.19,22 This relieves EPS like Parkinsonism and acute dystonia. This has led to the common strategy of In the patients treated with anticholinergic drugs, the giving trihexyphenidyl along with FGA in order to need for anticholinergic drugs is frequently not reduce EPS. Unfortunately this concomitant use of reassessed and many patients may remain on them trihexyphenidyl doesn't lessen the ability of FGA to for several years or even decades. WHO Heads of cause TD. It also causes the well- known side effects Centers Collaborating in WHO coordinated Studies associated with anticholinergic agents, such as dry on Biological Aspects of Mental Illness (1990) mouth, blurred vision, constipation, urinary issued a consensus statement against the retention and cognitive dysfunction.8 prophylactic use of anticholinergic drugs in patients receiving antipsychotics. 23 They recommended that “anticholinergic use be limited to when Parkinsonism arose and when other measures such as dose reduction or antipsychotic switching have failed.23Switching to lesser EPS-producing antipsychotics such as or clozapine is an option that may limit or avoid the use of anticholinergic drugs like trihexyphenidyl in some patients”.23 “The 2009 Schizophrenia Patient Outcomes Research Team (PORT) Treatment 24 FIGURE 3, D2 Antagonism and Anticholinergic Recommendations stated that the prophylactic use Agents.10 of anticholinergic drugs to reduce the incidence of

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EPS was not warranted in patients treated with SGA, drugs. Desmarais et al in a literature review about but should be evaluated on an individual basis for anticholinergic drugs in 201219, quoted a study by patients treated with FGA”.24 Drimer et al in 2004, who discontinued in 27 elderly in-patients, taking antipsychotics for DISCUSSION schizophrenia.Patients were administered ADAS- Trihexyphenidyl and other anticholinergic drugs Cog before and 10 days after discontinuation of have been used for the prophylaxis and the treatment biperiden. In total, 21 patients completed the study. of antipsychotic-induced EPS for decades. Studies Significant improvements on ADAS-Cog total score have shown the evidence for the effectiveness of and ideational praxis and orientation subscales were trihexyphenidyl in treatment of EPS like observed after the discontinuation of anticholinergic Parkinsonism and acute dystonia17but it worsens drugs.19, 27 18 TD. Naja & Halaby in a critical review of Stopping of anticholinergic drugs may influence anticholinergic use and misuse in psychiatry in 2017 compliance to antipsychotic drugs. Desmarais et al found out that anticholinergic drugs more in a literature review about anticholinergic drugs in particularly trihexyphenidyl can be more abused 19 7 2012 , quoted a study by Saran (1986), who than other antiparkinsonian agents. However it is observed that 9 out of 59 patients (18.3%) from a still poorly understood if this class of difference is health center who agreed to reduce or discontinue attributable to stimulatory properties of their anticholinergic drugs stopped taking their trihexyphenidyl as compared with the other antipsychotics. These patients didn't have clinical compounds, or simply because trihexyphenidyl is EPS before reduction or cessation of anticholinergic most commonly prescribed of all anticholinergic 28 7.25 drugs. Saran warned about the decreased drugs. The abusers of trihexyphenidyl were compliance with antipsychotic medicationsas a predominantly single, males, unemployed, of poor result of adverse effects following the reduction or socio-economic status and suffering from a more discontinuation of anticholinergic drugs.28 severe mental illness.7 The aim of the abuse is to achieve a high state, reducing the depressive and From the WHO Heads of Centers consensus negative symptoms secondary to the cholinergic statementagainst the prophylactic use of system hyperactivity.7,26Buhrich et al in 200011 in anticholinergic drugs in patients receiving 23 their study assessed misuse of anticholinergic drugs antipsychotics(1990) and PORT Treatment in a population of 50 patients with serious mental Recommendations about the prophylactic use of anticholinergic drugs to reduce the incidence of illness, who were assertively managed by a 24 community-based outreach team in Sydney, EPS, it is obvious that the prophylactic use of Australia. One third of the patients reported having anticholinergic drugs in patients receiving misused anticholinergic drugs in the previous antipsychotics is not justified. The department of month. All anticholinergic drugs were misused and psychiatry at Livingstone Central Hospital in collaboration with the hospital management and the trihexyphenidyl was misused most frequently. pharmacy department made a decision in February On direct questioning, the reason given was “to get 11 2018 to restrict the prescription of trihexyphenidyl to high”. In Zambia, anecdotal experience has been in the consultant psychiatrist only in order to reduce the line with the findings of these studies as prophylactic use of trihexyphenidyl. It was decided trihexyphenidyl has been the most commonly that each patient presenting with EPS will be prescribed anticholinergic drug by the mental health examined by the psychiatrist who will decide about professionals in Zambia. use of trihexyphenidyl from case to case basis. It was Trihexyphenidyl and other anticholinergic drugs are noted that majority of patients who were using associated with cognitive impairment in aging trihexyphenidyl didn't need it. Many patients patients,20,21 however the cognitive impairments demanded for trihexyphenidyl without even having usually improve after the discontinuation of the

136 Medical Journal of Zambia, Vol. 46 (2): 133 - 139 (2019) any EPS. They were given awareness about abuse ABBREVIATIONS potential and harmful effects of trihexyphenidyl by the health staff. This has been successful in EPS: , FGA: First drastically reducing the average monthly generation antipsychotics, SGA: Second generation consumption of trihexyphenidyl from 1350(5mg) antipsychotics, TD: ,PORT: tablets in 2017 to about less than 100(5mg) tablets in Patient outcomes research team, ADAS-cog: 2018. Alzheimer's disease assessment scale-cognitive subscale, WHO: World Health Organization CONCLUSION Trihexyphenidyl and other anticholinergic drugs DECLARATIONS have been used for prophylaxis and treatment of Ethical Approval antipsychotic-induced EPS for decades, 19 they are, however, associated with adverse effects, notably on Not applicable in case of review article. cognition, and can worsen TD. There is also strong potential for abuse associated with trihexyphenidyl. Competing Interest There is generally no need to start an anticholinergic The author declare that he has no competing drugs when a patient is prescribed antipsychotics. interests. For patients who are already on anticholinergic drugs, discontinuation of these drugs should be Funding considered in patients with stable EPS. Discontinuing anticholinergic drugs may improve No funding was received for publication of this TD, cognition, and perhaps psychiatric symptoms.19 article. Anticholinergic drugs can be considered only in individuals with significant EPS when dose ACKNOWLEDGEMENTS reduction and switching strategies have proven I am very grateful to my wife Ayesha Khalid for her ineffective, or when the side effects are acute or continuous assistance and support in the write up of severe. Three months of anticholinergic drugs this article. Special thanks to the management of treatment has been considered as adequate time Livingstone Central Hospital for their support. period after which an attempt for discontinuation 19 should take place. REFERENCES RECOMMENDATIONS 1. Insel TR. Rethinking schizophrenia. Nature 1. For patients taking FGA the prophylactic use of 2010; 468: 187-193. anticholinergic drugs like trihexyphenidyl is not 2. Ogino S, Miyamoto S, Miyake N, Yamaguchi N. recommended. Trihexyphenidyl can only be Benefits and limits of anticholinergic use in used if patient manifests EPS. So the decision to schizophrenia: focusing on its effect on use trihexyphenidyl should be determined on cognitive function; Psychiatry & Clinical case-by case basis. Neurosciences 2014; 68: 37-49. 2. For patients taking SGA, prophylactic use of 3. Miyake N, Miyamoto S, Jarskog LF. New trihexyphenidyl is not recommended. serotonin/ dopamine antagonists for the 3. Continued use of trihexyphenidyl should be re- treatment of schizophrenia. Clin. Schizophr. evaluated in patients with controlled symptoms Relat. Psychoses 2012; 6: 122-133. every 3 months. 4. Sadock BJ, Virginia AS. Synopsis of Psychiatry, 4. Older patients or patients with high risk of Behavioral Sciences/ Clinical Psychiatry. 10th cognitive disorder who use trihexyphenidyl ed. Philadelphia, USA. LippincottWilliams & should consider discontinuation due to high risk Wilkins 2007; 467-498. of cognitive decline and dementia

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